Biomimetic lung-targeting vehicle coupled with cryo-shocked leukocyte and inflammation-anchored liposome for drug delivery and anti-inflammation in treatment of acute pneumonia.

Acute pneumonia is a severe pulmonary inflammation, and it is critical to promptly suppress the dysregulated inflammatory responses to prevent mortality. Glucocorticoids are the first-line therapeutic drugs but with poor tissue selectivity and dose-dependent adverse effects. In this work, cryo-leukocyte, an autologous cell-derived immunosuppressor, was created by leveraging the cryo-shocking technology by the quick shock of normal leukocytes with liquid nitrogen. After coupling with aICAM-1 functionalized liposomes, this micro/nano composite system could achieve efficient and prompt inflammation alleviation in acute pneumonia. The engineered cryo-leukocytes were of well biocompatibility after evaluation of blood toxicity, tissue toxicity, acute toxicity and long-term biosafety for over 6 months, etc. Cryo-leukocytes preserved similar cellular receptors as normal leukocytes, capable of recognizing and binding inflammatory cytokines but without activation of immune cascade, thus exhibiting obvious anti-inflammation efficacy by acting as 'mixed cytokines antibodies'. The immunosuppression efficacy of cryo-leukocytes was also superior than that of its sub-group cells of cryo-neutrophil, cryo-monocyte and cryo-lymphocyte, due to relative wide protein expressions that are related to the immune responses. Besides, cryo-leukocytes coupled with aICAM-1 functionalized liposome exhibited obvious anchoring effect in inflammation sites by the interaction of ICAM-1 antibody and ICAM-1 molecules that were over-expressed on inflammatory pulmonary endothelial cells, thus served as superior drug lung-targeting vehicle to maximally enhance the accumulation of traditional Chinese and Western medicines in the lungs. A total of 68.1% of drug signals could be observed in lung tissues compared with other major organs after intravenous injection, significantly higher than that of micro-sized drug-loaded cryo-leukocyte (18.6%) and nano-sized drug-loaded aICAM-1-liposome (12.2%). In a lipopolysaccharide-induced acute pneumonia mice model, the drug-loaded cryo-leukocyte achieved superior anti-inflammation efficacy with 87.5% survival of mice after treatment.